Project Summary Colorectal cancer (CRC) is the leading cause of cancer death and is one of the most preventable cancers. Cyclooxygenase-2 (COX-2) expression increases in CRC, and inhibition of its activity by chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors suppresses CRC development. However, increased side effects due to chronic use of NSAIDs and COX-2 inhibitors limit their potential use in chemoprevention and chemotherapy of CRC. Recently, it has been proposed that 5-lipoxygenase (5-LOX) promotes, while 15-LOX inhibits, colorectal tumorigenesis. Therefore, to prevent CRC development, it is important to identify means to inhibit COX-2 and 5-LOX and stimulate 15-LOX with minimal side effects. Glucocorticoids (GCs) are the most potent endogenous COX-2 inhibitors, and their actions are down-regulated by type 2 11ss-hydroxysteroid dehydrogenase (11ssHSD2), which inactivate GCs. GCs also inhibit the 5-LOX pathway but stimulate the 15-LOX pathway. 11ssHSD2 is primarily expressed in classic aldosterone-sensitive epithelia such as in the kidney and colon, but is also expressed in small intestine. Elevation of 11ssHSD2 is associated with tumorigenesis. We have found that 11ssHSD2 inhibition suppresses COX-2 expression in kidney cortex. We hypothesize that 11ssHSD2 inhibition will inhibit the COX-2 and 5-LOX pathways but stimulate the 15-LOX pathway by elevating tumor intracellular levels of active GC and will thereby reduce colorectal tumorigenesis. We have three specific aims in the current proposal: Aim 1 will determine the preventive and therapeutic effects of 11ssHSD2 inhibition in a mouse model of intestinal polyposis (Min mouse) and the preventive effect of 11ssHSD2 inhibition in CT26 tumor metastasis; Aim 2 will study the mechanisms of 11ssHSD2 regulation of colorectal tumorigenesis; and Aim 3 will investigate the relative importance of 5-LOX, 15-LOX, and COX-2 pathway in 11ssHSD2 inhibition-mediated inhibition of adenoma development. Completion of this current proposal may point to new strategies for CRC chemoprevention and chemotherapy because of the following advantages: 1. Glycyrrhizic acid (GA), a compound contained in licorice, is a powerful 11ssHSD2 inhibitor and is nontoxic; 2). Due to its restricted expression, 11ssHSD2 inhibition is predicted to suppress CRC development without the potential cardiovascular risks posed by chronic use of COX-2 inhibitors; 3). GCs suppress COX-2, but not COX-1 expression. Therefore, 11ssHSD2 inhibition will suppress CRC development without the potential side effects due to COX-1 inhibition by NSAIDs; 4) 11ssHSD2 inhibition-mediated intracellular GC elevation may also inhibit colorectal tumorigenesis through inhibition of the 5-LOX pathway and stimulation of the 15-LOX pathway.